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Title: 3-(N,N-Diacylamino)quinazolin-4(3H)-ones : preparation, stereostructure and application in kinetic resolution of amines
Author: Al-Sehemi, Abdullah G. M.
Awarding Body: University of Leicester
Current Institution: University of Leicester
Date of Award: 2001
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3-Amino-2-[(S)-1-tert-butyldimethylsilyloxy-2-methylpropyl)quinazolin-4(3 H)-one was prepared from L-valine in six steps without the requirement for chromatography and used to prepare a number of 3-monoacylaminoquinazolinones (MAQs) by reaction with acid chlorides. The barrier to rotation around the N-N bond in these MAQs (~16 kcal/mol) is sufficient for it to constitute a chiral axis on the NMR timescale though not on the real timescale in solution. N,N-Diacylation of 3-aminoquinazolinones results in the formation of 3-diacylaminoquinazolinones (DAQs). When the two N-acyl groups of the imide in the DAQs are not identical, the N--N bond becomes a chiral axis with the two planes containing the quinazolinone and imide moieties orthogonal to one another as shown by X-ray crystal structures for twelve of these DAQs. The barrier to N--N bond rotation is sufficiently high to allow separation of diastereoisomers (atropisomers) when there is an additional chiral centre present either in an acyl group or in the Q-C2 substituent of the DAQ. These DAQs are highly selective acylating agents for the less sterically hindered of two secondary amines and, in enantiopure form, are highly enantioselective acylating agents for racemic amines, even under conditions of stoichiometry (1 eq. DAQ: 2 eq. amine) thus allowing recovery of the derivatised amine enantiomer and unreacted amine enantiomer. In these kinetic resolutions the presence of the N--N chiral axis was shown to be mandatory for high enantioselectivity to result. Where competitive attack of the racemic amine on both N-acyl groups of the DAQ occurred, it was found that each enantiomer reacted with a different N-acyl group (parallel kinetic resolution). Of particular interest were DAQs bearing homochiral N-acyl substituents [(S)-2-acetoxypropanoyl] for which separation of diastereoisomers was not required. The N-N bond in these DAQs is still a chiral axis because the most stable conformation of the imide moiety has an exo/endo orientation of the carbonyl groups which is much preferred over the alternative endo/exo as revealed by NMR spectroscopy. Consequently these DAQs are also enantioselective acylating agent for amines. For 3-(N-2-acetoxypropanoyl-N-acyl)aminoquinazolinones a single exo/endo conformation is present in solution in some cases but an interconverting exo/endo &lrhar2; endo/exo mixture in others. The imide conformational preferences in both classes of 2-acetoxypropanoyl-containing DAQs above were ascribed to the presence of a high conformational preference within the 2-acetoxypropanoyl group itself. In their reaction with amines, the rates of reaction of 3 sets of 2-acetoxypropanoyl-containing DAQs were correlated with the orientation of the (2-acetoxypropanoyl) methyl group in their crystal structures. It was concluded that the stereostructures in the crystal and in solution were essentially the same. This result should allow an understanding of the origin of the high enantioselectivity in these acylations with the prospect of increasing it to even higher levels by rational means.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available